Lecture 4 – Principles of Chemotherapy

General Principles
a) Gompertzian kinetics
a. Increasing growth rate
b. Logarithmic phase (exponential phase) – short doubling times
c. Deceleration
d. Plateau phase – time to double is prolonged
b) Cell kill hypothesis – constant fraction of tumor cells are killed with each CT cycle
a. Bulk tumor reduction needed at high # of cancer cells
i. Surgery
ii. Irradiation
iii. Chemotherapy
b. Chemotherapy – consistent doses & consistent intervals → most consistent
tumor killing
i. Multidrug
c. Immunotherapy – greatest benefit once tumor is clinically undetectable
c) Types of drugs
a. Antineoplastics
i. Cytotoxic chemotherapy
ii. Hormonal agents
iii. Immunotherapy
iv. Cancer vaccines
1. Cytokines
v. Monoclonals
vi. Targeted molecules – tyrosine kinase inhibitors
b. Supportive drugs
i. Hematopoietic growth factors – filgrastim, EPO
ii. Analgesics
c. Cell cycle non-specific - active against cells that are actively cycling AND cells in
G0
i. More effective when given as large dose (dose-dependent killing)
ii. Used for ablating bone marrow prior to stem cell transplant
iii. e.g. alkylating agents
d. Cell cycle specific – active only during specific cycle
i. More effective when given on a prolonged schedule / continuous infusion
(time-dependent killing)
ii. Effectiveness also increases with increasing frequency
iii. e.g. paclitaxel, 5-FU
d) Chemotherapy regimen design
a. Combinations of anticancer drugs
b. Drug should be active against tumor as single agent
c. Non-overlapping toxicities
d. Use optimal dose (maximally tolerated)
 e. Schedule treatment at optimal intervals
i. Drugs may be specific to certain parts of cell cycle
ii. G1 > S > G2 > M in terms of length
1. Mitosis is 30 min to 1 hr
e) Drug resistance
a. Increased gene expression
i. Increased expression of DNA repair enzymes
ii. Gene amplification of target
1. Methotrexate promotes synthesis of stable DHFR enzymes
b. MDRs (efflux pumps)
c. Target protein mutations
i. T790M mutation in EGFR → changes binding site
d. Enhanced drug metabolism
e. Kinetic resistance – cancer cells remain in G0
f) Overcoming drug resistance
a. ↑ drug dose or dose intensity with rescue mechanisms
i. Deliver high dose chemotherapy to ablate tumor, then perform
autologous bone marrow transplant
b. Inhibit MDR p-glycoprotein pump activity e.g. Verapamil
c. Module drug-enzyme complexes
d. Recruit quiescent cells back into cell cycle
e. Target cancer stem cells / cancer-initiating cells